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SOD1 binds copper and zinc ions and is one of three superoxide dismutases responsible for destroying free superoxide radicals in the body. The encoded isozyme is a soluble cytoplasmic and mitochondrial intermembrane space protein, acting as a homodimer to convert naturally occurring, but harmful, superoxide radicals to molecular oxygen and hydrogen peroxide.[3] Hydrogen peroxide can then be broken down by another enzyme called catalase.

Mutations (over 150 identified to date) in this gene have been linked to familial amyotrophic lateral sclerosis.[6][7] However, several pieces of evidence also show that wild-type SOD1, under conditions of cellular stress, is implicated in a significant fraction of sporadic ALS cases, which represent 90% of ALS patients.[8] The most frequent mutation are A4V (in the U.S.A.) and H46R (Japan). In Iceland only SOD1-G93S has been found. The most studied ALS mouse model is G93A. Rare transcript variants have been reported for this gene.[3]

Virtually all known ALS-causing SOD1 mutations act in a dominant fashion; a single mutant copy of the SOD1 gene is sufficient to cause the disease. The exact molecular mechanism (or mechanisms) by which SOD1 mutations cause disease are unknown. It appears to be some sort of toxic gain of function, as many disease-associated SOD1 mutants (including G93A and A4V) retain enzymatic activity and Sod1 knockout mice do not develop ALS (although they do exhibit a strong age-dependent distal motor neuropathy).

A4V (alanine at codon 4 changed to valine) is the most common ALS-causing mutation in the U.S. population, with approximately 50% of SOD1-ALS patients carrying the A4V mutation.[9][10][11] Approximately 10 percent of all U.S. familial ALS cases are caused by heterozygous A4V mutations in SOD1. The mutation is rarely if ever found outside the Americas.

It was recently estimated that the A4V mutation occurred 540 generations (~12,000 years) ago. The haplotype surrounding the mutation suggests that the A4V mutation arose in the Asian ancestors of native Americans, who reached the Americas through the Bering Strait.[12]

The A4V mutant belongs to the WT-like mutants. Patients with A4V mutations exhibit variable age of onset, but uniformly very rapid disease course, with average survival after onset of 1.4 years (versus 3–5 years with other dominant SOD1 mutations, and in some cases such as H46R, considerably longer). This survival is considerably shorter than non-mutant SOD1 linked ALS.

H46R (histidine at codon 46 changed to arginine) is the most common ALS-causing mutation in the Japanese population, with about 40% of Japanese SOD1-ALS patients carrying this mutation. H46R causes a profound loss of copper binding in the active site of SOD1, and as such, H46R is enzymatically inactive. The disease course of this mutation is extremely long, with the typical time from onset to death being over 15 years.[13] Mouse models with this mutation do not exhibit the classical mitochondrial vacuolation pathology seen in G93A and G37R ALS mice and unlike G93A mice, defeciency of the major mitochondrial antioxidant enzyme, SOD2, has no effect on their disease course.[13]

G93A (glycine 93 changed to alanine) is a comparatively rare mutation, but has been studied very intensely as it was the first mutation to be modeled in mice. G93A is a pseudo-WT mutation that leaves the enzyme activity intact.[11] Because of the ready availability of the G93A mouse from Jackson Laboratory, many studies of potential drug targets and toxicity mechanisms have been carried out in this model. At least one private research institute (ALS Therapy Development Institute) is conducting large-scale drug screens exclusively in this mouse model. Whether findings are specific for G93A or applicable to all ALS causing SOD1 mutations is at present unknown. It has been argued that certain pathological features of the G93A mouse are due to overexpression artefacts, specifically those relating to mitochondrial vacuolation (the G93A mouse commonly used from Jackson Lab has over 20 copies of the human SOD1 gene).[14] At least one study has found that certain features of pathology are idiosyncratic to G93A and not extrapolatable to all ALS causing mutations.[13] Further studies have shown that the pathogenesis of the G93A and H46R models are clearly distinct; some drugs and genetic interventions that are highly beneficial/detrimental in one model have either the opposite or no effect in the other.[15][15][16][17]

SOD1: Vietnam veteran Tom White and his wife, Carla, needed some help laying 1,000 yards of sod at their Sedalia home, and Smith-Cotton High School football players volunteered to get the job done. Lending a hand were, front from left, Roberto Ramirez, ...

In a new study entitled “Acute traumatic brain injury does not exacerbate ALS in the SOD1 model” researchers report that a one-time traumatic injury to the brain is not an accelerating factor for amyotrophic lateral sclerosis progression. The study was ...

(For instance, $2.5 million is going to a University of Massachusetts researcher for the “Development of AAV-Mediated SOD1 Gene Silencing Therapy in ALS.”) To frame things in layman's terms: The largest chunk—67%, or $77 million—will go to research ...

Mutations in the SOD1 (superoxide dismutase-1) gene, which encodes a key protein important for the detoxification of motor neurons, accounts for approximately 12% of inherited ALS forms. After three days in culture, researchers found that the neurons ...

But he and colleagues have provided strong evidence for another hypothesis: that SOD1 mutations cause ALS by destabilizing the SOD1 protein structure. This leads to increased motion of the proteins, which Crane likened to “breathing.” This movement ...

The original study occurred within SOD1 gene mutations, but the team extended the research to test the effect of Retigabine on other iPS cell lines. The drug significantly reduced neuronal firing in every iPS line. 2. A new system of drug delivery may ...

... amyloid plaque loads in hippocampus and frontal cortex, as well as plasma AÎ²1-42 levels, were significantly reduced by MEL in a receptor-independent manner, in contrast to MEL's efficacy in reducing cortical antioxidant gene expression (Catalase ...

The second most common cause of inherited forms of ALS occur due to mutations in the SOD1 gene, which encodes a key protein important for the detoxification of motor neurons. It is not clear how mutant SOD1 protein contributes to ALS development.

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